Trends in the Care and Outcomes of Medicare Beneficiaries with Type 2 Diabetes, 2002–2011

Objective: To summarize characteristics of Medicare beneficiaries with type 2 diabetes and to describe changing trends in care and outcomes.Methods: We conducted a retrospective cohort study of a nationally representative 5% sample of fee-for-service Medicare beneficiaries 65 years and older with prevalent type 2 diabetes, between January 1, 2002, and December 31, 2011. The main outcome measures were diabetes-related screening tests, mortality, hospital admissions, dialysis, and lower extremity amputation.Results: The average age of Medicare beneficiaries with diabetes was 76.5 years, 56% were women, and 83% were white. Screening practices in beneficiaries with diabetes improved from 2002 to 2011, with rising rates of foot exams, renal screening, hemoglobin A1c tests, and lipid profile tests. The prevalence of nephropathy and neuropathy increased. Although inpatient admissions declined from 2002 to 2011, diabetes-related emergency department visits increased. Amputation and end-stage renal disease remained static, while 1-year mortality declined over the study period.Conclusion: In this medically complex group of patients with high comorbidity, we observed improvements in screening practices and room for further improvement. Although the mortality rate decreased, other outcomes did not improve consistently. Health care resource has changed over time, with decreased hospital admissions and increased emergency department visits.Abbreviations:CCW = Chronic Conditions Data WarehouseESRD = end-stage renal diseaseHbA1c = hemoglobin A1cHEDIS = Healthcare Effectiveness Data and Information SetICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification     

Can Newer Therapies Delay the Progression of Type 2 Diabetes Mellitus?

ObjectiveTo review the multifactorial and progressive nature of type 2 diabetes mellitus (T2DM), the consequences of its progression, and the potential of traditional and newer therapies to delay the progression of this disease.MethodsThe relevant literature is reviewed, and the mechanisms of action of novel agents for treatment of T2DM are discussed.ResultsThe global prevalence of diabetes has been increasing in recent decades, reaching near-epidemic proportions, and is projected to more than double by 2030. More than 90% of cases of diabetes in most countries consist of T2DM, but many individuals remain undiagnosed or are diagnosed only after their disease has progressed considerably. Inadequate glycemic control in a majority of patients with T2DM is due to the progressive nature of the disease, delay in initiating pharmacotherapy, and failure to intensify treatment more quickly in patients who do not achieve glycemic targets. Traditional oral therapies are usually effective at lowering hyperglycemia initially but do not prevent disease progression; thus, many patients ultimately require insulin. Furthermore, because most antidiabetic therapies are associated with weight gain or risk of hypoglycemia (or both), patients may not adhere to treatment recommendations.ConclusionA new therapeutic approach focuses on the use of the incretin hormone glucagon-like peptide-1. Analogues of this hormone delay the progression of β-cell dysfunction and promote β-cell regeneration in animal models. In clinical trials, they have been shown to improve glycemic control by increasing glucose-stimulated insulin secretion and suppressing glucagon secretion. At high concentrations, they also slow gastric emptying and increase satiety, which often promotes weight loss. Another approach is to inhibit the enzyme dipeptidyl-peptidase 4, which rapidly inactivates glucagon-like peptide- 1 and glucose-dependent insulinotropic polypeptide, thereby increasing endogenous incretin levels. (Endocr Pract. 2008;14:625-638)     

Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study

Backround

A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity.

Methodology/Results

Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2^nd phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits.

Conclusion

The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.     

Receipt of Glucose Testing and Performance of Two US Diabetes Screening Guidelines, 2007–2012

Background

Screening guidelines are used to help identify prediabetes and diabetes before implementing evidence-based prevention and treatment interventions. We examined screening practices benchmarking against two US guidelines, and the capacity of each guideline to identify dysglycemia.

Methods

Using 2007–2012 National Health and Nutrition Examination Surveys, we analyzed nationally-representative, cross-sectional data from 5,813 fasting non-pregnant adults aged ≥20 years without self-reported diabetes. We examined proportions of adults eligible for diagnostic glucose testing and those who self-reported receiving testing in the past three years, as recommended by the American Diabetes Association (ADA) and the US Preventive Services Task Force (USPSTF-2008) guidelines. For each screening guideline, we also assessed sensitivity, specificity, and positive (PPV) and negative predictive values in identifying dysglycemia (defined as fasting plasma glucose ≥100 mg/dl or hemoglobin A1c ≥5.7%).

Results

In 2007–2012, 73.0% and 23.7% of US adults without diagnosed diabetes met ADA and USPSTF-2008 criteria for screening, respectively; and 91.5% had at least one major risk factor for diabetes. Of those ADA- or USPSTF-eligible adults, about 51% reported being tested within the past three years. Eligible individuals not tested were more likely to be lower educated, poorer, uninsured, or have no usual place of care compared to tested eligible adults. Among adults with ≥1 major risk factor, 45.7% reported being tested, and dysglycemia yields (i.e., PPV) ranged from 45.8% (high-risk ethnicity) to 72.6% (self-reported prediabetes). ADA criteria and having any risk factor were more sensitive than the USPSTF-2008 guideline (88.8–97.7% vs. 31.0%) but less specific (13.5–39.7% vs. 82.1%) in recommending glucose testing, resulting in lower PPVs (47.7–54.4% vs. 58.4%).

Conclusion

Diverging recommendations and variable performance of different guidelines may be impeding national diabetes prevention and treatment efforts. Efforts to align screening recommendations may result in earlier identification of adults at high risk for prediabetes and diabetes.     

Improvements in Metabolic Control in Adults with Type 2 Diabetes Following Referral to a Diabetes Center, 2005–2010

Objective: We aimed to compare metabolic control in adults with diabetes in the general population to those newly referred to a diabetes center and after 1 year of specialty care.Methods: We performed a retrospective comparison of adults with diabetes aged ≥20 years data from the National Health and Nutrition Examination Survey (NHANES, n = 1,674) and a diabetes center (n = 3,128) from 2005–2010. NHANES participants represented the civilian, non-institutionalized U.S. population. Diabetes center referrals lived primarily around eastern Massachusetts. The proportion attaining targets for glycated hemoglobin A1c (A1c), blood pressure (BP), low-density lipoprotein (LDL) cholesterol, or all 3 (ABC control) and the proportion prescribed medications to lower A1c, BP, or cholesterol were evaluated.Results: Compared to the general sample, a smaller proportion of new diabetes center referrals had A1c <7% (<53 mmol/mol, 24% vs. 53%, P<.001), BP <130/80 mm Hg (38% vs. 50%, P<.001), and ABC control (5.6% vs. 17%, P<.001) but not LDL<100 mg/dL (<2.6 mmol/L, 54% vs. 53%, P = .65). After 1 year, more diabetes center referrals attained targets for A1c (40%), BP (38%), LDL (67%), and ABC control (15%) (P<.001 for all versus baseline). ABC control was not different between the general sample and diabetes center referrals at 1 year (P = .16). After 1 year, a greater percentage of diabetes center referrals compared to the general sample were prescribed medications to lower glucose (95% vs. 72%), BP (79% vs. 64%), and cholesterol (77% vs. 54%)(all P<.001).Conclusion: Compared to the general population, glycemic control was significantly worse for adults newly referred to the diabetes center. Within 1 year of specialty care, ABC control increased 270% in the setting of significant therapy escalation.Abbreviations:A1c = glycated hemoglobin A1cABC = composite of A1c, blood pressure, and cholesterolACEi = angiotensin-converting enzyme inhibitorARB = angiotensin receptor blockerBMI = body mass indexBP = blood pressureEHR = electronic health recordLDL = low-density lipoproteinNCHS = National Center for Health StatisticsNHANES = National Health and Nutrition Examination SurveyPCP = primary care provider     

The Effects of Empagliflozin,an SGLT2 Inhibitor,on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes

The novel sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic β-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and insulin mRNA expression were determined using commercial insulin ELISA kits and real-time quantitative polymerase chain reaction, respectively. Immunohistochemistry was used to investigate β-cell areas, β-cell proliferation, apoptosis of pancreatic β-cells, and reactive oxygen species production in the pancreatic β-cells. Results showed that glucose tolerance was significantly improved in streptozotocin-induced type 1 diabetic mice treated with empagliflozin. Empagliflozin-treated mice also showed an increase in insulin mRNA expression. Higher serum insulin levels were detected in mice treated with empagliflozin compared with the vehicle group. Immunohistochemistry indicated that β-cell area/total pancreatic area and the expression of cell proliferation marker Ki-67 (co-stained with insulin) were significantly enhanced by empagliflozin treatment. These effects were due, probably, to a reduction in apoptosis and reactive oxygen species in the pancreatic β-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving β-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic β-cell from glucotoxicity-induced oxidative stress.     

Soluble ST2 Associates with Diabetes but Not Established Cardiovascular Risk Factors: A New Inflammatory Pathway of Relevance to Diabetes?

Preliminary data mostly from animal models suggest the sST2/IL-33 pathway may have causal relevance for vascular disease and diabetes and thus point to a potential novel inflammatory link to cardiometabolic disease. However, the characterisation of sST2 levels in terms of metabolic or vascular risk in man is completely lacking. We sought to address this gap via a comprehensive analysis of risk factor and vascular correlates of sST2 in a cross-sectional study (pSoBid). We measured sST2 in plasma in 639 subjects and comprehensively related it to cardiovascular and diabetes risk factors and imaged atherosclerosis measures. Circulating sST2 levels increased with age, were lower in women and in highest earners. After adjusting for age and gender, sST2 levels associated strongly with markers of diabetes, including triglycerides [effect estimate (EE) per 1 standard deviation increase in sST2∶1.05 [95%CI 1.01,1.10]), liver function (alanine aminotransaminase [ALT] and γ-glutamyl transferase [GGT]: EE 1.05 [1.01,1.09] and 1.13 [1.07,1.19] respectively), glucose (1.02 [1.00,1.03]) and sICAM-1 (1.05 [1.02,1.07]). However, sST2 levels were not related to smoking, cholesterol, blood pressure, or atheroma (carotid intima media thickness, plaque presence). These results suggest that sST2 levels, in individuals largely without vascular disease, are related principally to markers associated with diabetes and ectopic fat and add support for a role of sST2 in diabetes. Further mechanistic studies determining how sST2 is linked to diabetes pathways may offer new insights into the inflammatory paradigm for type 2 diabetes.     

Effect of Diabetes Mellitus Type 2 on Salivary Glucose – A Systematic Review and Meta-Analysis of Observational Studies

Background

Early screening of type 2 diabetes mellitus (DM) is essential for improved prognosis and effective delay of clinical complications. However, testing for high glycemia often requires invasive and painful blood testing, limiting its large-scale applicability. We have combined new, unpublished data with published data comparing salivary glucose levels in type 2 DM patients and controls and/or looked at the correlation between salivary glucose and glycemia/HbA1c to systematically review the effectiveness of salivary glucose to estimate glycemia and HbA1c. We further discuss salivary glucose as a biomarker for large-scale screening of diabetes or developing type 2 DM.

Methods and Findings

We conducted a meta-analysis of peer-reviewed published articles that reported data regarding mean salivary glucose levels and/or correlation between salivary glucose levels and glycemia or HbA1c for type 2 DM and non-diabetic individuals and combined them with our own unpublished results. Our global meta-analysis of standardized mean differences on salivary glucose levels shows an overall large positive effect of type 2 DM over salivary glucose (Hedge''s g = 1.37). The global correlation coefficient (r) between salivary glucose and glycemia was large (r = 0.49), with subgroups ranging from medium (r = 0.30 in non-diabetics) to very large (r = 0.67 in diabetics). Meta-analysis of the global correlation between salivary glucose and HbA1c showed an overall association of medium strength (r = 0.37).

Conclusions

Our systematic review reports an overall meaningful salivary glucose concentration increase in type 2 DM and a significant overall relationship between salivary glucose concentration and associated glycemia/HbA1c values, with the strength of the correlation increasing for higher glycemia/HbA1c values. These results support the potential of salivary glucose levels as a biomarker for type 2 DM, providing a less painful/invasive method for screening type 2 DM, as well as for monitoring blood glucose levels in large cohorts of DM patients.     

Prevalence,Correlates, and Description of Self-Reported Diabetes in Brazilian Capitals – Results from a Telephone Survey

Introduction

The prevalence of diabetes is increasing worldwide. The objective of this study is to estimate the prevalence of self-reported diabetes in Brazilian adults and to describe its population correlates as well as the clinical characteristics of the reported cases.

Methods

We analyzed basic and supplementary data of 54.144 subjects participating in VIGITEL 2011 (Surveillance System for Risk and Protective Factors for Chronic Diseases), a telephone survey based on a probabilistic sample of subjects ≥18 years old residing in Brazilian state capitals and the Federal District. Estimates reported are weighted so as to represent the surveyed population.

Results

The prevalence of self-reported diabetes was 6.3% (95% CI 5.9–6.7), increasing markedly with age and nutritional status, and decreasing with level of education. Prevalence was higher among those self-declaring their race/color as black. Most cases (90%) reported the diagnosis being made at 35 years or older. The vast majority (99.8%) of self-reported cases informed having previously performed at least one glucose test, and 76% of those not reporting diabetes also informed having previously performed glucose testing. Most cases (92.6%) reported following some form of diabetes treatment, 79% taking medication.

Conclusion

The estimated prevalence of known diabetes found, 6.3%, is consistent with estimates given by international summaries. The additional data collected in VIGITEL 2011 regarding previous glucose testing and current treatment support the use of telephone-based information to monitor the prevalence of known diabetes in Brazilian capitals.     

Association Analysis of IGF2BP2, KCNJ11, and CDKAL1 Polymorphisms with Type 2 Diabetes Mellitus in a Moroccan Population: A Case–Control Study and Meta-analysis

Associations with type 2 diabetes mellitus have been identified for variants CDKAL1 rs7756992, KCNJ11 rs5219, and IGF2BP2 rs4402960 in different populations. In a case–control study of 250 unrelated Moroccan diabetic patients and 250 healthy controls, we used TaqMan allelic discrimination assays to genotype the three SNPs and meta-analysis to investigate the association between the polymorphisms and diabetes in Arab populations. The results showed a significant diabetes association only with the variant rs4402960 of the IGF2BP2 gene under additive 2 (GG vs. TT; p = 0.009) and recessive (TT vs. GG+GT; p = 0.003) models. Meta-analysis indicated significant association between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased risk of diabetes in Arab populations. According to our results, the case–control study and meta-analysis revealed a significant association between the IGF2BP2 rs4402960 variant and type 2 diabetes in Moroccan and Arab populations.     

Association of NFκβ, TNFα, IL-6, IL-1β, and LPL Polymorphisms with Type 2 Diabetes Mellitus and Biochemical Parameters in a Mexican Population

Biochemical Genetics - Chronic low-grade inflammation is strongly related to the etiology of diabetes mellitus type 2 (T2DM), and the expression of inflammatory cytokines may be modulated by...     

Who Will Manage American Patients With Diabetes? Residents’ Career Preferences and Perceptions of Diabetes Care

ObjectiveTo identify the factors that encourage or discourage internal medicine and pediatric residents regarding specializing in endocrinology with a focus on diabetes.MethodsWe conducted an electronic survey of internal medicine and pediatric residents using a $10 participation incentive. A total of 653 residents responded to the survey (estimated response rate of 9.2%)—626 from residency programs that were contacted for our survey and 27 from referrals.ResultsAmong internal medicine and pediatric residents surveyed, 39 respondents (6.0%) planned to specialize in endocrinology, and 27 of these (4.1% of total respondents) planned to focus on diabetes. “Intellectual satisfaction, ” “emotional satisfaction, ” and “work-life balance” were identified by respondents as the most important factors in their choice of a specialty, with ratings of 5.5, 5.4, and 5.3 on a 6-point Likert scale. Among these factors identified as most important to a medical career, endocrinology with a focus on diabetes scored poorly with regard to intellectual and emotional satisfaction but received high ranking with regard to lifestyle. With regard to other factors, endocrinology was rated negatively on “compensation, ” “number of procedures, ” and “patient adherence to prescribed treatment.” Exposure to diabetes during training had no major influence on the decision to enter endocrinology.ConclusionEndocrinology with a focus on diabetes care is not an attractive specialty for most internal medicine and pediatric residents. Therefore, new strategies to attract residents to the field of diabetes care are needed. (Endocr Pract. 2011;17:235-239)     

Exposure to p,p′-DDE: A Risk Factor for Type 2 Diabetes

Background

Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes.

Methodology/Principal Findings

A case-control study was performed within a well-defined cohort of women, age 50–59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p′-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p′-DDE).

Conclusions/Significance

The results from the present case-control study, including a follow-up design, confirms that p,p′-DDE exposure can be a risk factor for type 2 diabetes.     

Symptoms of Emotional,Behavioral, and Social Difficulties in the Danish Population of Children and Adolescents with Type 1 Diabetes – Results of a National Survey

Objective

To assess the prevalence of psychological difficulties in Danish children and adolescents with type 1 diabetes using both child/adolescent and caregiver reports, and to investigate associations between these symptoms and metabolic control, adherence, and quality of life.

Research Design and Method:

A total of 786 children and adolescents (8–17 years) recruited through the Danish Registry of Childhood Diabetes completed subscales of the Beck''s Youth Inventories (BYI-Y), while 910 caregivers completed the Strength and Difficulties Questionnaire (SDQ). The participants also completed questionnaires assessing adherence and quality of life. BYI-Y and SDQ responses were compared with results from normative samples.

Results

Children with diabetes generally reported a lower level of symptoms of depression and anxiety, while older adolescents in most cases were comparable to the normative samples. However, the numbers of patients with elevated scores were similar to normative groups, especially regarding the proportion of participants with ‘Extremely elevated’ scores. Caregivers of children and adolescents with diabetes generally reported the prevalence of elevated scores on the SDQ to exceed the prevalence observed in the norm sample – particularly with regard to older boys. Both BYI-Y and SDQ responses were significantly correlated with HbA_1c, adherence, and quality of life.

Conclusions

This study finds Danish children and adolescents with diabetes to report lower or comparable levels of emotional difficulties compared to norms, while caregiver reports are less positive. The results therefore support the value of a multi-informant approach to the assessment of symptoms of psychological difficulty in girls and boys with diabetes.     

Progressive Induction of Type 2 Diabetes: Effects of a Reality–Like Fructose Enriched Diet in Young Wistar Rats

Purpose

The aim of this study was to characterize short and medium-lasting effects of fructose supplementation on young Wistar rats. The diet was similar to actual human consumption.

Methods

Three week old male rats were randomly divided into 2 groups: control (C; n = 16), fructose fed (FF; n = 16) with a fructose enriched drink for 6 or 12 weeks. Bodyweight, fasting glycemia and systolic blood pressure were monitored. Glucose tolerance was evaluated using an oral glucose tolerance test. Insulinemia was measured concomitantly and enable us to calculate insulin resistance markers (HOMA-IR, Insulin Sensitivity Index for glycemia: ISI-gly). Blood chemistry analyses were performed.

Results

After six weeks of fructose supplementation, rats were not overweight but presented increased fasting glycemia, reduced glucose tolerance, and lower insulin sensitivity compared to control group. Systolic blood pressure and heart weight were also increased without any change in renal function (theoretical creatinine clearance). After twelve weeks of fructose supplementation, FF rats had increased bodyweight and presented insulin resistance (higher HOMA-IR, lower ISI-gly). Rats also presented higher heart volume and lower ASAT/ALAT ratio (presumed liver lesion). Surprisingly, the Total Cholesterol/Triglycerides ratio was increased only after six weeks of fructose supplementation, predicting a higher LDL presence and thus a higher risk of developing cardiovascular disease. This risk was no longer present after twelve weeks of a fructose enriched diet.

Conclusion

On young Wistar rats, six weeks of fructose supplementation is sufficient to induce signs of metabolic syndrome. After twelve weeks of fructose enriched diet, rats are insulin resistant. This model enabled us to study longitudinally the early development of type 2 diabetes.     

Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus

A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1β (ERO1β) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic β cells. It has recently been demonstrated that ERO1β promotes insulin biogenesis in β cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1β is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1β expression is paradoxically decreased in β cells despite the indications of increased ER stress. However, overexpression of ERO1β in β cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1β overexpression caused ER stress in the β cells. Insulin contents were decreased in the β cells that overexpressed ERO1β, leading to impaired insulin secretion in response to glucose stimulation. These data indicate the importance of the fine-tuning of the ER redox state, the disturbance of which would compromise the function of β cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus.